US4346100A - Phenoxy acetic acid derivative, its preparation and therapeutic use - Google Patents
Phenoxy acetic acid derivative, its preparation and therapeutic use Download PDFInfo
- Publication number
- US4346100A US4346100A US05/897,287 US89728778A US4346100A US 4346100 A US4346100 A US 4346100A US 89728778 A US89728778 A US 89728778A US 4346100 A US4346100 A US 4346100A
- Authority
- US
- United States
- Prior art keywords
- acetic acid
- preparation
- phenoxy acetic
- acid derivative
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Definitions
- the new derivative of this invention is [2-isopropyl-4-(2-thenoyl)-5-methyl]-phenoxy acetic acid, which has the formula: ##STR1##
- the new compound has the general formula C 17 H 18 O 4 S 1 and has a molecular weight of 318. It is a white crystalline product melting at 147°-148° C. (Tottoli), and insoluble in water, soluble in ethanol, chloroform, dimethylsulphoxide and transcutanol.
- Tottoli white crystalline product melting at 147°-148° C.
- the compound is particularly interesting for its therapeutic activities in the field of choleresis. It may be used as such per os or under the form of its soluble salts with alkali metals for intravenous administration.
- the technic used was that one described in J. Pharmacologie, Paris, 1971, 2, 2, 175-182 on anaesthesied female rats; in this experimentation were determined 1, 2, 3 and 4 hours later per os administration for treated rats compared with non-treated rats, the percentage of variation of bile flow (A), the percentage of variation of amount of protein in the bile flow (B) and the percentage of variation of cholesterol amount (C).
- a first batch of 10 rats was anaesthesied and zero time taken 15' after the anaesthesy; 1, 2, 3 and 4 hours later were measured the bile flows, the amounts of protein and cholesterol; the average figures obtained were retained as a basis for comparison.
- the compound according to the invention does not induce the liberation of cholesterol at a high rate; this is nevertheless an advantage as demonstrated by the publication FEUILLETS DE BIOLOGIE, 1977-Vol. XVIII-No. 97-page 65 to 70.
- each unit may comprise from 0.05 to 0.25 g. of active ingredient, acid form; for intravenous administration the preferred form is one alkali metal salt of the compound with a dosage of 0.25 to 0.50 g. of active ingredient per phial.
- Usual posology in human administration comprises 0.05 to 0.25 g. per diem for oral route and 0.25 to 0.50 g. per diem for intravenous route.
- This invention accordingly provides a therapeutic composition
- a therapeutic composition comprising the compound according to the invention or an alkali metal salt of the same in admixture with one or more pharmacologically acceptable diluents or carriers.
- the new compound may be prepared according to this invention by reacting 2-isopropyl-4-( ⁇ -thenoyl)-5-methylphenol with ethyl monobromoacetate under reflux in a ketonic solvent. From the resulting ethyl ester, the compound of the invention may be directly obtained by hydrolysis.
- 2-isopropyl-4-( ⁇ -thenoyl)-5-methylphenol may be obtained by reacting thymol on thenoyl chloride in the presence of aluminium chloride in acetylene tetrachloride.
- Corresponding alkali metal salts are obtained from the acid by the usual routes.
Abstract
This invention relates to a new phenoxy acetic acid derivative, to a method for its preparation and to therapeutic compositions containing it.
Description
The new derivative of this invention is [2-isopropyl-4-(2-thenoyl)-5-methyl]-phenoxy acetic acid, which has the formula: ##STR1##
The new compound has the general formula C17 H18 O4 S1 and has a molecular weight of 318. It is a white crystalline product melting at 147°-148° C. (Tottoli), and insoluble in water, soluble in ethanol, chloroform, dimethylsulphoxide and transcutanol.
The compound is particularly interesting for its therapeutic activities in the field of choleresis. It may be used as such per os or under the form of its soluble salts with alkali metals for intravenous administration.
A toxicity study undertaken on this compound has given per os LD 50 figures of about 0.8 g. per kilo for female mice and 2.35 g/kg. for female rats. Sodium and potassium salts are a little less toxic.
Complete comparative pharmacological studies (on rats) undertaken, for the choleresis, on the compound of this invention and on sodium dehydrocholate, have shown a very favourable activity of the compound of this invention, with respect to the reference compound.
The technic used was that one described in J. Pharmacologie, Paris, 1971, 2, 2, 175-182 on anaesthesied female rats; in this experimentation were determined 1, 2, 3 and 4 hours later per os administration for treated rats compared with non-treated rats, the percentage of variation of bile flow (A), the percentage of variation of amount of protein in the bile flow (B) and the percentage of variation of cholesterol amount (C).
A first batch of 10 rats was anaesthesied and zero time taken 15' after the anaesthesy; 1, 2, 3 and 4 hours later were measured the bile flows, the amounts of protein and cholesterol; the average figures obtained were retained as a basis for comparison.
Similar measures were thus made for 4 batches of each 6 rats treated per os by 4 different doses of the compound of the invention and, in each base, the percentage of variation was calculated with respect to the corresponding values of non-treated animals.
The same work was then done with 3 batches of each 6 rats treated by 3 different doses of sodium dehydrocholate and the calculated figures obtained for both experimentations were reported in the accompanying table.
For sodium dehydrocholate doses retained were the generally accepted one of 100 mg/kg, one lower and one higher.
For the compound of the invention, preliminary tests having lead to the figures of 25 and 50 mg/kg as favourable doses, one lower and one higher doses were also retained for safety purposes.
The compound according to the invention does not induce the liberation of cholesterol at a high rate; this is nevertheless an advantage as demonstrated by the publication FEUILLETS DE BIOLOGIE, 1977-Vol. XVIII-No. 97-page 65 to 70.
Turning now to the form of adminstration, for oral route, tablets and gelatine capsules are preferred; each unit may comprise from 0.05 to 0.25 g. of active ingredient, acid form; for intravenous administration the preferred form is one alkali metal salt of the compound with a dosage of 0.25 to 0.50 g. of active ingredient per phial.
Usual posology in human administration comprises 0.05 to 0.25 g. per diem for oral route and 0.25 to 0.50 g. per diem for intravenous route.
This invention accordingly provides a therapeutic composition comprising the compound according to the invention or an alkali metal salt of the same in admixture with one or more pharmacologically acceptable diluents or carriers.
The new compound may be prepared according to this invention by reacting 2-isopropyl-4-(α-thenoyl)-5-methylphenol with ethyl monobromoacetate under reflux in a ketonic solvent. From the resulting ethyl ester, the compound of the invention may be directly obtained by hydrolysis.
2-isopropyl-4-(α-thenoyl)-5-methylphenol may be obtained by reacting thymol on thenoyl chloride in the presence of aluminium chloride in acetylene tetrachloride.
This invention is illustrated by the following example:
Into a one-liter reactor, fitted with stirring, warming and cooling means there were poured:
31.44 g. (0.12 mole) of 2-isopropyl-4-(α-thenoyl)-5-methyl phenol 400 ml. of methyl ethyl ketone
33 ml. of ethyl bromoacetate
24 g. (0.19 mole) of potassium carbonate, and some potassium iodide crystals.
The mixture was then stirred and refluxed for four hours. Then it was evaporated to dryness, extracted with 400 ml of diethyl ether, washed with water, once more evaporated to dryness and recrystallized from hexane.
There were thus obtained 38.4 g. of the ethyl ester of the compound of the invention (yield: 85%).
38.4 g (0.106 mole) of this ester, 22 g. (0.55 mole) of pure sodium hydroxide and 600 ml of ethanol were added to a one-liter reactor fitted with stirring and warming means, and then refluxed for three hours, evaporated to about 400 ml, cooled and mixed under stirring with 34 ml of acetic acid (a 10% excess).
After 30 minutes of stirring, the mixture was filtrated and the precipitate was washed and recrystallized from benzene.
There were thus obtained 28.6 g (yield: 85% of the product, [2-isopropyl-4-(α-thenoyl)-5-methyl]-phenoxy acetic acid, the structure of which was confirmed by analysis and U.V. spectrum.
Corresponding alkali metal salts are obtained from the acid by the usual routes.
__________________________________________________________________________
Doses
1 hour 2 hours 3 hours 4 hours
Product mg/kg
A B C A B C A B C A B C
__________________________________________________________________________
Product of the
12.5
+42 +59 -17
+16
+2 +8 +10
-13
-3 +10
+13
+3
invention
25.0
+52 +58 +35
+26
+40 +27
+13
+7 +10
+6 +16
+10
50.0
+62 +77 -1 +49
+50.5
+24
+30
+36
+18
+21
+26
-1
75.0
+87 +103
-- +75
+78 -- +60
+56
-- +44
+47
--
Sodium 50.0
+33 +24 +14
+16
+10 +7.5
+11
+5 +9.5
+7 -2 +4
dehydrocholate
100.0
+77 + 50
+10
+18
+20 -2 +7 +5.5
+4 +6 +36
+8
150.0
+144
+98 -- +48
+32 -- +23
+11
-- +2 +11
--
__________________________________________________________________________
Claims (1)
1. A therapeutic composition comprising a choloretically effective amount of a compound selected from the group consisting of [2-isopropyl-4-(2-thenoyl)-5-methyl]-phenoxy acetic acid and alkali metal salts thereof, together with a pharmaceutically acceptable carrier therefor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB16789/77A GB1569404A (en) | 1977-04-22 | 1977-04-22 | (2-isopropyl-4-(2'-theonyl)-5-methyl) phenoxy acetic acid |
| GB16789/77 | 1977-04-22 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/097,037 Continuation US4254162A (en) | 1977-04-22 | 1979-11-21 | Phenoxy acetic acid derivative, its preparation and therapeutic use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4346100A true US4346100A (en) | 1982-08-24 |
Family
ID=10083695
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/897,287 Expired - Lifetime US4346100A (en) | 1977-04-22 | 1978-04-17 | Phenoxy acetic acid derivative, its preparation and therapeutic use |
| US06/097,037 Expired - Lifetime US4254162A (en) | 1977-04-22 | 1979-11-21 | Phenoxy acetic acid derivative, its preparation and therapeutic use |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/097,037 Expired - Lifetime US4254162A (en) | 1977-04-22 | 1979-11-21 | Phenoxy acetic acid derivative, its preparation and therapeutic use |
Country Status (29)
| Country | Link |
|---|---|
| US (2) | US4346100A (en) |
| JP (1) | JPS53132555A (en) |
| AR (1) | AR215300A1 (en) |
| AT (1) | AT359487B (en) |
| AU (1) | AU518054B2 (en) |
| BE (1) | BE865422A (en) |
| CA (1) | CA1109886A (en) |
| CH (1) | CH629795A5 (en) |
| DE (1) | DE2817399C3 (en) |
| DK (1) | DK174578A (en) |
| EG (1) | EG13312A (en) |
| ES (1) | ES469022A1 (en) |
| FI (1) | FI63396C (en) |
| FR (2) | FR2387651A1 (en) |
| GB (1) | GB1569404A (en) |
| HK (1) | HK66580A (en) |
| IE (1) | IE46803B1 (en) |
| IN (1) | IN147778B (en) |
| LU (1) | LU79345A1 (en) |
| MX (1) | MX4992E (en) |
| MY (1) | MY8100237A (en) |
| NL (1) | NL171583C (en) |
| NO (1) | NO147449C (en) |
| NZ (1) | NZ186912A (en) |
| OA (1) | OA05940A (en) |
| PH (1) | PH13547A (en) |
| PT (1) | PT67919B (en) |
| SE (1) | SE425606B (en) |
| ZA (1) | ZA781746B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4017632A (en) * | 1975-10-22 | 1977-04-12 | Centre European De Recherches Pharmacologiques C.E.R.P.H.A. | Phenoxyacetic acid derivatives |
| US4072705A (en) * | 1975-02-12 | 1978-02-07 | Orchimed S.A. | Phenylmethylphenoxy propionic acid esters |
| US4115402A (en) * | 1977-06-17 | 1978-09-19 | Merck & Co., Inc. | 2,3-Dichloro-4-[(substituted-sulfonyl)-phenoxy]-acetic acids |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE757001A (en) * | 1969-10-10 | 1971-03-16 | Cerpha | HETEROCYCLIC DERIVATIVES OF PHENOXY ACETIC ACIDS AND THEIR PREPARATION |
| CA1007643A (en) * | 1972-10-24 | 1977-03-29 | Janssen Pharmaceutica Naamloze Vennootschap | Aroyl-substituted phenylacetic acid derivatives |
| US3958004A (en) * | 1974-04-23 | 1976-05-18 | Merck & Co., Inc. | Phenoxyacetic acid derivatives as uricosuric agents |
| US3969508A (en) * | 1974-11-27 | 1976-07-13 | Smithkline Corporation | Lowering the concentration of plasma triglycerides |
| FR2342726A1 (en) * | 1976-02-18 | 1977-09-30 | Smithkline Corp | Diuretic and hypotensive compsns. - contg. triamterene and thenoyl-dichloro-phenoxyacetic acid |
-
1977
- 1977-04-22 GB GB16789/77A patent/GB1569404A/en not_active Expired
-
1978
- 1978-03-28 ZA ZA00781746A patent/ZA781746B/en unknown
- 1978-03-29 CH CH334178A patent/CH629795A5/en not_active IP Right Cessation
- 1978-03-29 BE BE186354A patent/BE865422A/en not_active IP Right Cessation
- 1978-03-30 IN IN233/DEL/78A patent/IN147778B/en unknown
- 1978-03-31 LU LU79345A patent/LU79345A1/en unknown
- 1978-04-06 AT AT244178A patent/AT359487B/en not_active IP Right Cessation
- 1978-04-07 NZ NZ186912A patent/NZ186912A/en unknown
- 1978-04-07 NL NLAANVRAGE7803728,A patent/NL171583C/en not_active IP Right Cessation
- 1978-04-11 EG EG249/78A patent/EG13312A/en active
- 1978-04-11 FI FI781100A patent/FI63396C/en not_active IP Right Cessation
- 1978-04-11 AU AU34970/78A patent/AU518054B2/en not_active Expired
- 1978-04-14 OA OA56470A patent/OA05940A/en unknown
- 1978-04-17 US US05/897,287 patent/US4346100A/en not_active Expired - Lifetime
- 1978-04-19 CA CA301,502A patent/CA1109886A/en not_active Expired
- 1978-04-19 PT PT67919A patent/PT67919B/en unknown
- 1978-04-20 JP JP4598478A patent/JPS53132555A/en active Granted
- 1978-04-20 FR FR7811641A patent/FR2387651A1/en active Granted
- 1978-04-20 FR FR7811642A patent/FR2387976A1/en active Granted
- 1978-04-20 DE DE2817399A patent/DE2817399C3/en not_active Expired
- 1978-04-20 DK DK174578A patent/DK174578A/en not_active Application Discontinuation
- 1978-04-20 SE SE7804526A patent/SE425606B/en unknown
- 1978-04-21 NO NO781402A patent/NO147449C/en unknown
- 1978-04-21 IE IE797/78A patent/IE46803B1/en unknown
- 1978-04-21 ES ES469022A patent/ES469022A1/en not_active Expired
- 1978-04-21 MX MX787033U patent/MX4992E/en unknown
- 1978-04-24 PH PH21041A patent/PH13547A/en unknown
- 1978-05-09 AR AR272092A patent/AR215300A1/en active
-
1979
- 1979-11-21 US US06/097,037 patent/US4254162A/en not_active Expired - Lifetime
-
1980
- 1980-11-20 HK HK665/80A patent/HK66580A/en unknown
-
1981
- 1981-12-30 MY MY237/81A patent/MY8100237A/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4072705A (en) * | 1975-02-12 | 1978-02-07 | Orchimed S.A. | Phenylmethylphenoxy propionic acid esters |
| US4017632A (en) * | 1975-10-22 | 1977-04-12 | Centre European De Recherches Pharmacologiques C.E.R.P.H.A. | Phenoxyacetic acid derivatives |
| US4115402A (en) * | 1977-06-17 | 1978-09-19 | Merck & Co., Inc. | 2,3-Dichloro-4-[(substituted-sulfonyl)-phenoxy]-acetic acids |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| STCF | Information on status: patent grant |
Free format text: PATENTED CASE |